PROJECT SUMMARY/ABSTRACT This project's long-term goal is to understand asthma's immunological mechanisms. Airway inflammation in patients with asthma is generally characterized by increased lymphocytes producing type 2 cytokines. However, the mechanisms involved in persistent and/or recurrent production of type 2 cytokines in the airways are not entirely understood. Notable progress regarding the mechanisms of type 2 immunity has been made in the past several years. Group 2 innate lymphoid cells (ILC2s) that rapidly produce large quantities of type 2 cytokines have been identified and are implicated in the innate arm of type 2 immunity. More recent findings suggest the ability of ILC2s to regulate the adaptive arm of immunity and their high degree of plasticity. Thus, the primary objective of this renewal application is to translate these new discoveries in the basic science of ILC2s to the immunologic mechanisms of asthma. We will test the hypothesis that ILC2s play a vital role in persistent and recurrent airway inflammation in asthma. In Aim 1, we will determine the roles of lung ILC2s in a chronic airway inflammation model in mice. By using a model in which mice are repeatedly exposed to natural airborne allergens, we will dissect the roles for ILC2s and Th2-type CD4+ T cells in chronic airway inflammation. In Aim 2, we will elucidate the genetic and functional plasticity of lung ILC2s in mice. The immune system of mice housed in a regular specific pathogen- free environment is similar to human neonates. Through the use of a recently developed novel mouse model that replicates a human adult-like immune system, we will investigate the functional plasticity of lung ILC2s in that environment and how their abilities to promote type 2 inflammation are modulated. In Aim 3, we will investigate the roles of ILC2s in a chronic airway disease in humans. In patients, chronic rhinosinusitis (CRS) is often associated with asthma. By using an established clinical protocol to evaluate CRS patients during a natural exacerbation of the disease, we will investigate how functions of ILC2s are regulated dynamically in the disease process. This application integrates mechanistic studies in mice and a proof-of-concept study in humans. It represents collaborative efforts among basic science and translational immunologists and clinician investigators. The tools and technical expertise necessary to accomplish this project are in place. Therefore, the proposed studies will likely provide fundamental information regarding type 2 airway inflammation recurrence and persistence in patients with asthma and ILC2s involvement. Clarification of the immunological mechanisms involved in the disease process will lead to development of novel strategies for the prevention and treatment of asthma and related chronic airway disorders.